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Hiroko Hashimoto, Naohiro Nomura, Wakana Shoda, Kiyoshi Isobe, Hiroaki Kikuchi, Kouhei Yamamoto, Takuya Fujimaru, Fumiaki Ando, Takayasu Mori, Tomokazu Okado, Tatemitsu Rai, Shinichi Uchida, Eisei Sohara
OBJECTIVE: Metformin is an antidiabetic drug that is widely used to treat patients with diabetes mellitus. Recent studies have reported that treatment with metformin not only improved blood glucose levels but also reduced blood pressure. However, it remains unclear how metformin reduces blood pressure. We hypothesized that metformin affects sodium reabsorption in the kidneys. METHODS: Urinary sodium excretion and expression of renal sodium transporters were examined in 8-week-old male C57BL/6 mice with acute and chronic treatment of metformin...
March 3, 2018: Metabolism: Clinical and Experimental
Autumn N Harris, P Richard Grimm, Hyun-Wook Lee, Eric Delpire, Lijuan Fang, Jill W Verlander, Paul A Welling, I David Weiner
Background Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), the most common RTA observed, but the molecular mechanisms underlying the associated metabolic acidosis are incompletely understood. We sought to determine whether hyperkalemia directly causes metabolic acidosis and, if so, the mechanisms through which this occurs. Methods We studied a genetic model of hyperkalemia that results from early distal convoluted tubule (DCT)-specific overexpression of constitutively active Ste20/SPS1-related proline-alanine-rich kinase (DCT-CA-SPAK)...
February 26, 2018: Journal of the American Society of Nephrology: JASN
Gul Hassan Sethar, Aisha Almoghawi, Nargis Khan, Wehad Altourah, Najat Mohammed Ashour
Pseudohypoaldosteronism (PHA) type II is an extremely rare disorder which presents with hypertension, hyperkalemia, and normal anion gap metabolic acidosis. PHA II is also known as familial hyperkalemic hypertension, Gordon syndrome, and chloride shunt syndrome. PHA II is an autosomal dominant disorder and is caused by mutation in WNK1, WNK4, CULLIN3, KLHL3, OSR, SPAK gene. The expression of these proteins is limited to the distal convoluted tube and collecting duct of the kidney. PHA II usually responds to salt restriction and thiazide diuretics...
March 2018: Journal of the College of Physicians and Surgeons—Pakistan: JCPSP
Chloé Rafael, Christelle Soukaseum, Véronique Baudrie, Perrine Frère, Juliette Hadchouel
Mutations of the gene encoding WNK1 [With No lysine (K) kinase 1] or WNK4 cause Familial Hyperkalemic Hypertension (FHHt). Previous studies have shown that the activation of SPAK (Ste20-related Proline/Alanine-rich Kinase) plays a dominant role in the development of FHHt caused by WNK4 mutations. The implication of SPAK in FHHt caused by WNK1 mutation has never been investigated. To clarify this issue, we crossed WNK1+/FHHt mice with SPAK knock-in mice in which the T-loop Thr243 residue was mutated to alanine to prevent activation by WNK kinases...
February 19, 2018: Scientific Reports
Yoskaly Lazo-Fernandez, Paul A Welling, Susan M Wall
Alpha-ketoglutarate (αKG) is a citric acid cycle intermediate and a glutamine catabolism product. It is also the natural ligand of OXGR1, a Gq-protein coupled receptor expressed on the apical membrane of intercalated cells. In the CCD, Cl- /HCO3 - exchange increases upon αKG binding to the OXGR1. To determine the signaling pathway(s) by which αKG stimulates Cl- absorption, we examined αKG-stimulated Cl- absorption in isolated perfused mouse CCDs. αKG increased electroneutral Cl- absorption in CCDs from wild type mice, but had no effect on Cl- absorption in pendrin KO mice...
February 7, 2018: American Journal of Physiology. Renal Physiology
Michael L Green, Jeremy J Moeller, Judy M Spak
BACKGROUND: Cognitive psychology studies demonstrate that subjects who attempt to recall information show better learning, retention, and transfer than subjects who spend the same time studying the same material (test-enhanced learning, TEL). We systematically reviewed TEL interventions in health professions education. METHODS: We searched 13 databases, 14 medical education journals, and reference lists. Inclusion criteria included controlled studies of TEL that compared TEL to studying the same material or to a different TEL strategy...
February 1, 2018: Medical Teacher
Yih-Sheng Yang, Jian Xie, Sung-Sen Yang, Shih-Hua Lin, Chou-Long Huang
The Na+-Cl- cotransporter (NCC) in distal convoluted tubule (DCT) plays important roles in renal NaCl reabsorption. Current hypothesis for the mechanism of regulation of NCC focuses on WNK4 and intracellular Cl- concentration ([Cl-]i). WNK kinases bind Cl- and Cl- binding decreases the catalytic activity. It is believed that hypokalemia under low K+ intake decreases [Cl-]i to activate WNK4, which thereby phosphorylates and stimulates NCC through activation of SPAK. However, increased NCC activity and apical NaCl entry would mitigate the fall in [Cl-]i...
January 31, 2018: American Journal of Physiology. Renal Physiology
Quentin Bazot, Kostas Paschos, Martin J Allday
Epstein-Barr virus (EBV) establishes latent infection in human B cells and is associated with a wide range of cancers. The EBV nuclear antigen 3 (EBNA3) family proteins are critical for B cell transformation and function as transcriptional regulators. It is well established that EBNA3A and EBNA3C co-operate in the regulation of cellular genes. Here we demonstrate that the gene STK39 is repressed only by EBNA3A. This is the first example of a gene regulated only by EBNA3A in EBV-transformed lymphoblastoid cell lines (LCLs) without the help of EBNA3C...
January 24, 2018: Journal of Virology
Mohammed Zubaerul Ferdaus, James A McCormick
Autosomal dominant mutations in Cullin3 (Cul3) cause the most severe form of Familial Hyperkalemic Hypertension (FHHt). Cul3 mutations cause skipping of exon 9 which results in an internal deletion of 57 amino acids from the CUL3 protein (CUL3-∆9). The precise mechanism by which this altered form of CUL3 causes FHHt is controversial. CUL3 is a member of the Cullin-Ring ubiquitin Ligase (CRL) family which mediates ubiquitination and thus degradation of cellular proteins including With-no-lysine [K] kinases (WNKs)...
January 17, 2018: American Journal of Physiology. Renal Physiology
Naohiro Nomura, Wakana Shoda, Yuanlong Wang, Shintaro Mandai, Taisuke Furusho, Daiei Takahashi, Moko Zeniya, Eisei Sohara, Tatemitsu Rai, Shinichi Uchida
The sodium-chloride cotransporter (NCC) has been identified as a key molecule regulating potassium balance. The mechanisms of NCC regulation during low extracellular potassium concentrations have been studied in vitro. These studies have shown that hyperpolarization increased chloride efflux, leading to the activation of chloride-sensitive WNK kinases and their downstream molecules, including STE20/SPS1-related proline/alanine-rich kinase (SPAK) and NCC. However, this mechanism was not studied in vivo Previously, we developed the barttin hypomorphic mouse ( Bsndneo/neo mice), expressing very low levels of barttin and ClC-K channels, because barttin is an essential ß-subunit of ClC-K...
January 11, 2018: Bioscience Reports
Viktor N Tomilin, Oleg Zaika, Arohan R Subramanya, Oleh Pochynyuk
The renal collecting duct contains two distinct cell types, principal and intercalated cells, expressing potassium Kir4.1/5.1 (KCNJ10/16) and chloride ClC-K2 (ClC-Kb in humans) channels on their basolateral membrane, respectively. Both channels are thought to play important roles in controlling systemic water-electrolyte balance and blood pressure. However, little is known about mechanisms regulating activity of Kir4.1/5.1 and ClC-K2/b. Here, we employed patch clamp analysis at the single channel and whole cell levels in freshly isolated mouse collecting ducts to investigate regulation of Kir4...
November 13, 2017: Pflügers Archiv: European Journal of Physiology
Rainelli Koumangoye, Eric Delpire
SPAK (STE20/SPS1-related proline/alanine-rich kinase) regulates Na+ and Cl- reabsorption in the distal convoluted tubule, and possibly in the thick ascending limb of Henle. This kinase phosphorylates and activates the apical Na-Cl cotransporter in the DCT. Western blot analysis reveals that SPAK in kidney exists as a full-length protein as well as shorter fragments that might affect NKCC2 function in the TAL. Recently, we showed that kidney lysates exerts proteolytic activity towards SPAK, resulting in the formation of multiple SPAK fragments with possible inhibitory effects on the kinase...
November 2017: Physiological Reports
Yan Liu, Sandeep Dhall, Anthony Castro, Alex Chan, Raquelle Alamat, Manuela Martins-Green
Wound healing is a complex process that involves sequential phases that overlap in time and space and affect each other dynamically at the gene and protein levels. We previously showed that insulin accelerates wound healing by stimulating faster and regenerative healing. One of the processes that insulin stimulates is an increase in monocyte/macrophage chemotaxis. In this study, we performed experiments in vivo and in vitro to elucidate the signaling transduction pathways that are involved in insulin-induced monocyte/macrophage chemotaxis...
November 3, 2017: Biology Open
Nicholas J Herkert, Scott N Spak, Austen Smith, Jasmin K Schuster, Tom Harner, Andres Martinez, Keri C Hornbuckle
Passive air samplers equipped with polyurethane foam (PUF-PAS) are frequently used to measure persistent organic pollutants (POPs) in ambient air. Here we present and evaluate a method to determine sampling rates (RS), and the effective sampling volume (Veff), for gas-phase chemical compounds captured by a PUF-PAS sampler deployed anywhere in the world. The method uses a mathematical model that requires only publicly available hourly meteorological data, physical-chemical properties of the target compound, and the deployment dates...
November 2, 2017: Environmental Science. Processes & Impacts
Leslie C Conway, Ross A Cardarelli, Yvonne E Moore, Karen Jones, Lisa J McWilliams, David J Baker, Matthew P Burnham, Roland W Bürli, Qi Wang, Nicholas J Brandon, Stephen J Moss, Tarek Z Deeb
The K+/Cl- co-transporter (KCC2) is selectively expressed in the adult nervous system, and allows neurons to maintain low intracellular Cl- levels. Thus, KCC2 activity is an essential prerequisite for fast hyperpolarizing synaptic inhibition mediated by type A γ-aminobutyric acid receptors (GABAA), which are Cl- permeable, ligand-gated ion channels. Consistent with this, deficits in the activity of KCC2 lead to epilepsy, and are also implicated in neurodevelopmental disorders, neuropathic pain, and schizophrenia...
November 1, 2017: Journal of Biological Chemistry
Ivan Torre-Villalvazo, Luz Graciela Cervantes-Perez, Lilia G Noriega, Jose V Jimenez, Norma Uribe, Maria Chavez-Canales, Claudia Tovar-Palacio, Braulio A Marfil-Garza, Nimbe Torres, Norma A Bobadilla, Armando R Tovar, Gerardo Gamba
The STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) controls the activity of the electroneutral cation-chloride cotransporters (SLC12 family) and thus physiological processes such as modulation of cell volume, intracellular chloride concentration [Cl-]i and transepithelial salt transport. Modulation of SPAK kinase activity may have an impact on hypertension and obesity as STK39, the gene encoding SPAK has been suggested as a hypertension and obesity susceptibility gene. In fact, the absence of SPAK activity in mice in which the activating threonine in the T-loop was substituted by alanine (SPAK-KI mice) is associated with decreased blood pressure; however its consequences in metabolism have not been explored...
October 24, 2017: American Journal of Physiology. Endocrinology and Metabolism
Marianne Brodmann, Koen Keirse, Dierk Scheinert, Lubomir Spak, Michael R Jaff, Randy Schmahl, Pei Li, Thomas Zeller
OBJECTIVES: This study sought to evaluate the safety and effectiveness of a paclitaxel-coated drug-coated balloon (DCB) for the treatment of patients with de novo in-stent restenosis (ISR). BACKGROUND: Treatment of patients with ISR remains a challenge. Current strategies are plagued by high rates of recurrent restenosis and need for reintervention. The best intervention for ISR remains to be elucidated. METHODS: The IN.PACT Global study is an independently adjudicated multicenter, prospective, single-arm study that enrolled 1,535 subjects with symptomatic atherosclerotic disease of the superficial femoral and/or popliteal arteries, including de novo ISR lesions...
October 23, 2017: JACC. Cardiovascular Interventions
Marika Markkanen, Anastasia Ludwig, Stanislav Khirug, Evgeny Pryazhnikov, Shetal Soni, Leonard Khiroug, Eric Delpire, Claudio Rivera, Matti S Airaksinen, Pavel Uvarov
The neuron-specific K-Cl cotransporter KCC2 maintains the low intracellular chloride concentration required for the fast hyperpolarizing responses of the inhibitory neurotransmitters γ-aminobutyric acid (GABA) and glycine. The two KCC2 isoforms, KCC2a and KCC2b differ by their N-termini as a result of alternative promoter usage. Whereas the role of KCC2b in mediating the chloride transport is unequivocal, the physiological role of KCC2a in neurons has remained obscure. We show that KCC2a isoform can decrease the intracellular chloride concentration in cultured neurons and attenuate calcium responses evoked by application of the GABAA receptor agonist muscimol...
November 15, 2017: Brain Research
Luz G Cervantes-Perez, Maria Castaneda-Bueno, Jose V Jimenez, Norma Vazquez, Lorena Rojas-Vega, Dario R Alessi, Norma A Bobadilla, Gerardo Gamba
OBJECTIVE: The hypertensive effect of angiotensin II (AngII), a peptide hormone, is dependent on its intrarenal actions and the activation of the renal Na-Cl cotransporter (NCC), by AngII requires integrity of the with no lysine kinase/STE20-proline alanine-rich kinase (WNK/SPAK) signaling pathway. Here, we analyzed if the integrity of the WNK/SPAK pathway is required for AngII infusion to induce arterial hypertension. METHODS: We tested the effect of AngII or aldosterone administration on the blood pressure and on pNCC/NCC ratio in SPAK knock-in mice in which the kinase and thus NCC cannot be activated by WNK kinases...
September 14, 2017: Journal of Hypertension
Chih-Chin Shih, Lin-Pin Hsu, Mei-Hui Liao, Sung-Sen Yang, Shung-Tai Ho, Chin-Chen Wu
Vasoplegia impedes therapeutic interventions to restore vascular tone, leading to severe hypotension, poor tissue perfusion, and multiple organ failure in septic shock. High levels of circulating nitric oxide (NO) play a crucial role in endotoxin-induced vascular hyporeactivity. Proinflammatory cytokines have been implicated in the induction of inducible NO synthase and overproduction of NO. Anti-inflammatory therapy can diminish NO formation and improve vascular hyporeactivity in septic shock. STE20/SPS1-realted proline/alanine-rich kinase (SPAK) has been reported to activate mitogen-activated protein kinase and contribute to intestinal inflammation...
November 5, 2017: European Journal of Pharmacology
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